Azithromycin is indicated for the treatment of the following infections when known or likely to be due to one or more susceptible microorganisms (see section 5.1):

- bronchitis

- community-acquired pneumonia

- sinusitis

- pharyngitis/tonsillitis (see section 4.4 regarding streptococcal infections)

- otitis media

- skin and soft tissue infections

- uncomplicated genital infections due to Chlamydia trachomatis and Neisseria gonorrhoeae.

Considerations should be given to official guidance regarding the appropriate use of antibacterial agents.

Posology:

Azimac Tablets should be given as a single daily dose.

In common with many other antibiotics Azimac Tablets should be taken at least 1 hour before or 2 hours after food.

Children over 45 kg body weight and adults, including elderly patients:

The total dose of azithromycin is 1500 mg which should be given over three days (500 mg once daily).

In uncomplicated genital infections due to Chlamydia trachomatis, the dose is 1000 mg as a single oral dose. For susceptible Neisseria gonorrhoeae the recommended dose is 1000 mg or 2000 mg of azithromycin in combination with 250 mg or 500 mg ceftriaxone according to local clinical treatment guidelines. For patients who are allergic to penicillin and/or cephalosporins, prescribers should consult local treatment guidelines.

Paediatric population:

In children under 45 kg body weight: Azimac Tablets are not suitable for children under 45 kg.

Renal impairment:

No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10 - 80 ml/min). Caution should be exercised when azithromycin is administered to patients with severe renal impairment (GFR < 10 ml/min) (see section 4.4 and section 5.2).

Hepatic impairment:

Since azithromycin is metabolised in the liver and excreted in the bile, the drug should not be given to patients suffering from severe liver disease. No studies have been conducted regarding treatment of such patients with azithromycin (see section 4.4).

Method of administration:

Azimac Tablets are for oral administration only.

Hypersensitivity

As with erythromycin and other macrolides, serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), Acute Generalized Exanthematous Pustulosis (AGEP) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.

Hepatotoxicity

Since the liver is the principal route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with significant hepatic disease. Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with azithromycin (see section 4.8). Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products.

In case of signs and symptoms of liver dysfunction, such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver function tests/ investigations should be performed immediately. Azithromycin administration should be stopped if liver dysfunction has emerged.

Ergot derivatives

In patients receiving ergot derivatives, ergotism has been precipitated by co-administration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administrated.

Prolongation of the QT interval

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarisation (see section 4.8); therefore caution is required when treating patients:

• With congenital or documented QT prolongation

• Currently receiving treatment with other active substance known to prolong QT interval such as antiarrhythmics of Classes Ia and III, cisapride and terfenadine

• With electrolyte disturbance, particularly in case of hypokalaemia and hypomagnesemia

• With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

Superinfection

As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms including fungi is recommended.

Clostridium difficile associated diarrhoea

Clostridium difficile associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhoea to fatal colitis. Strains of C. difficile producing hypertoxin A and B contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. Therefore, CDAD must be considered in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. Discontinuation of therapy with azithromycin and the administration of specific treatment for C. difficile should be considered.

Streptococcal infections

Penicillin is usually the first choice for treatment of pharyngitis/tonsillitis due to Streptococcus pyogenes and also for prophylaxis of acute rheumatic fever. Azithromycin is in general effective against streptococcus in the oropharynx, but no data are available that demonstrate the efficacy of azithromycin in preventing acute rheumatic fever.

Renal impairment:

In patients with severe renal impairment (GFR <10 ml/min) a 33% increase in systemic exposure to azithromycin was observed (see section 5.2).

Myasthenia gravis

Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy (see section 4.8).

Diabetes

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicinal product contains sulphur dioxide which may rarely cause severe hypersensitivity reactions and bronchospasm.

Azimac tablets are for oral administration only.

The long-term azithromycin exposure following HSCT may include risks that exceed the anticipated benefits. Safety of prophylactic long-term azithromycin treatment in this patient group is questioned.

 “A clinical trial ALLOZITHRO that investigated long-term azithromycin to prevent bronchiolitis obliterans syndrome (BOS) in patients who underwent allogenic Hematopoietic Stem Cell Transplantation (HSCT) for hematological malignancy was terminated early after an increased rate of mortality and relapses of haematological malignancies was seen in patients taking azithromycin compared with placebo”.

Antacids: In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall bioavailability was seen, although peak serum concentrations were reduced by approximately 24%. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously.

Cetirizine: In healthy volunteers, co-administration of a 5-day regimen of azithromycin with 20 mg cetirizine at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.

Didanosine (Dideoxyinosine): Co-administration of 1200 mg/day azithromycin with 400 mg/day didanosine in six HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared to placebo.

Digoxin and colchicine: concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-glycoprotein substrates such as digoxin are administered concomitantly, the possibility of elevated serum digoxin concentrations should be considered. Clinical monitoring, and possibly serum digoxin levels, during treatment with azithromycin and after its discontinuation are necessary.

Zidovudine: Single 1000 mg doses and multiple 1200 mg or 600 mg doses of azithromycin had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.

Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.

Ergot derivatives: Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended (see section 4.4).

Pharmacokinetic studies have been conducted between azithromycin and the following drugs known to undergo significant cytochrome P450 mediated metabolism.

Atorvastatin: Co-administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay).

Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.

Cimetidine: In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was seen.

Coumarin-type oral anticoagulants: In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single dose of 15 mg warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to co-administration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants.

Ciclosporin: In a pharmacokinetic study with healthy volunteers who were administered a 500 mg/day oral dose of azithromycin for 3 days and were then administered a single 10 mg/kg oral dose of ciclosporin, the resulting ciclosporin C_max and AUC_0-5 were found to be significantly elevated (by 24% and 21% respectively), however no significant changes were seen in AUC_0-∞. Consequently, caution should be exercised before considering concurrent administration of these drugs. If co-administration of these drugs is necessary, ciclosporin levels should be monitored and the dose adjusted accordingly.

Efavirenz: Co-administration of a single dose of 600 mg azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.

Fluconazole: Co-administration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the co-administration of fluconazole, however, a clinically insignificant decrease in C_max (18%) of azithromycin was observed.

Indinavir: Co-administration of a single dose of 1200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for 5 days.

Methylprednisolone: In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.

Midazolam: In healthy volunteers, co-administration of 500mg/day azithromycin for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single dose of 15mg midazolam.

Nelfinavir: Co-administration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects were observed and no dose adjustment was required.

Rifabutin: Co-administration of azithromycin and rifabutin did not affect the serum concentrations of either drug. Neutropenia was observed in subjects receiving concomitant treatment of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with azithromycin has not been established (see section 4.8.).

Sildenafil: In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and C_max, of sildenafil or its major circulating metabolite.

Terfenadine: Pharmacokinetic studies have reported no evidence of an interaction between azithromycin and terfenadine. There have been rare cases reported where the possibility of such an interaction could not be entirely excluded; however there was no specific evidence that such an interaction had occurred.

Theophylline: There is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are co-administered to healthy volunteers.

Triazolam: In 14 healthy volunteers, co-administration of 500mg azithromycin on Day 1 and 250 mg on Day 2 with 0.125 mg triazolam on Day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole: Co-administration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days with 1200mg azithromycin on Day 7 had no significant effect on peak concentrations, total exposure or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies.

Pregnancy

Animal reproduction studies have been performed at doses up to moderately maternally toxic dose concentrations. In these studies, no evidence of harm to the foetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.

Breast-feeding

There are no data on secretion in breast milk. As many drugs are excreted in human milk, azithromycin should not be used in the treatment of a lactating woman unless the physician feels that the potential benefits justify the potential risks to the infant.

There is no evidence to suggest that Azimac may have an effect on a patient's ability to drive or operate machinery.

Azimac is well tolerated with a low incidence of side effects.

The section below lists the adverse reactions identified through clinical trial experience and postmarketing surveillance by system organ class and frequency. Adverse reactions identified from post-marketing experience are included in italics. The frequency grouping is defined using the following convention: Very common (≥1/10); Common (≥ 1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥ 1/10,000 to <1/1,000); Very Rare (< 1/10,000); and Not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions possibly or probably related to azithromycin based on clinical trial experience and post-marketing surveillance:

Infections and Infestations

Uncommon (≥1/1,000 to <1/100)

Candidiasis, oral candidiasis, vaginal infection

Not known (cannot be estimated from available data)

Pseudomembranous colitis (see section 4.4)

Blood and Lymphatic System Disorders

Uncommon (≥ 1/1,000 to < 1/100)

Leukopenia, neutropenia

Not known (cannot be estimated from available data)

Thrombocytopenia, haemolytic anaemia

Immune System Disorders

Uncommon (≥1/1,000 to <1/100)

Angioedema, hypersensitivity

Not known (cannot be estimated from available data)

Anaphylactic reaction (see section 4.4)

Metabolism and Nutrition Disorders

Common (> 1/100, < 1/10)

Anorexia

Psychiatric Disorders

Uncommon (≥1/1,000 to <1/100)

Nervousness

Rare (> 1/10000, < 1/1000)

Agitation

Not known (cannot be estimated from available data)

Aggression, anxiety

Nervous System Disorders

Common (> 1/100, < 1/10)

Dizziness, headache, paraesthesia, dysgeusia

Uncommon (≥1/1,000 to <1/100)

Hypoaesethesia, somnolence, insomnia

Not known (cannot be estimated from available data)

Syncope, convulsion, psychomotor hyperactivity, anosmia, ageusia, parosmia, Myasthenia gravis (see section 4.4).

Eye Disorders

Common (> 1/100, < 1/10)

Visual impairment

Ear and Labyrinth Disorders

Common (> 1/100, < 1/10)

Deafness

Uncommon (≥1/1,000 to <1/100)

Hearing impaired, tinnitus

Rare (> 1/10000, < 1/1000)

Vertigo

Cardiac Disorders

Uncommon (≥1/1,000 to <1/100)

Palpitations

Not known (cannot be estimated from available data)

Torsades de pointes (see section 4.4), arrhythmia (see section 4.4) including ventricular tachycardia

Vascular Disorders

Not known (cannot be estimated from available data)

Hypotension

Gastrointestinal Disorders

Very common (≥1/10)

Diarrhoea, abdominal pain, nausea, flatulence

Common (> 1/100, < 1/10)

Vomiting, dyspepsia

Uncommon (> 1/1000, < 1/100)

Gastritis, constipation

Not known (cannot be estimated from available data)

Pancreatitis, tongue discolouration

Hepatobiliary Disorders

Uncommon (> 1/1000, < 1/100)

Hepatitis

Rare (> 1/10000, < 1/1000)

Hepatic function abnormal

Not known (cannot be estimated from available data)

Hepatic failure (see section 4.4), which has rarely resulted in death, hepatitis fulminant, hepatic necrosis, jaundice cholestatic

Skin and Subcutaneous Tissue Disorders

Common (> 1/100, < 1/10)

Pruritus and rash

Uncommon (> 1/1000, < 1/100)

SJS, photosensitivity reaction, urticarial

Rare (≥1/10,000 to <1/1,000)

Acute Generalized Exanthematous Pustulosis (AGEP)*^§

Drug reaction with eosinophilia and systemic symptoms (DRESS)*^§

Not known (cannot be estimated from available data)

TEN, erythema multiforme

Musculoskeletal, Connective Tissue Disorders

Common (> 1/100, < 1/10)

Arthralgia

Renal and Urinary Disorders

Not known (cannot be estimated from available data)

Renal failure acute, nephritis interstitial

General disorders and Administration Site Conditions

Common (> 1/100, < 1/10)

Fatigue

Uncommon (> 1/1000, < 1/100)

Chest pain, oedema, malaise, asthenia

Investigations

Common (> 1/100, < 1/10)

Lymphocyte count decreased, eosinophil count increased, blood bicarbonate decreased

Uncommon (> 1/1000, < 1/100)

Aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, blood urea increased, blood creatinine increased, blood potassium abnormal

Not known (cannot be estimated from available data)

Electrocardiogram QT prolonged (see section 4.4)

*ADR identified post-marketing

^§ADR frequency represented by the estimated upper limit of the 95% confidence interval calculated using the “Rule of 3”.

Reporting of suspected adverse reactions

-       National Pharmacovigilance and Drug Safety Center (NPC)

o Fax: +966-11-205-7662

o To call the executive management of vigilance and crisis management: +966-11-2038222 ext.: 2353 – 2356 – 2317 – 2354 – 2334 – 2340

o Toll-free: 8002490000

o E-mail: npc.drug@sfda.gov.sa

o Website: www.sfda.gov.sa/npc

Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea. In the event of overdose, the administration of medicinal charcoal and general symptomatic treatment and supportive measures are indicated as required.

General properties

Pharmacotherapeutic group: Antibacterials for systemic use. ATC code: J01FA10

Mode of action:

Azimac is a macrolide antibiotic belonging to the azalide group. The molecule is constructed by adding a nitrogen atom to the lactone ring of erythromycin A. The chemical name of azithromycin is 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A. The molecular weight is 749.0. The mechanism of action of azithromycin is based upon the suppression of bacterial protein synthesis by means of binding to the ribosomal 50S sub-unit and inhibition of peptide translocation.

Mechanism of resistance:

Resistance to azithromycin may be inherent or acquired. There are three main mechanisms of resistance in bacteria: target site alteration, alteration in antibiotic transport and modification of the antibiotic.

Azithromycin demonstrates cross resistance with erythromycin resistant gram positive isolates. A decrease in macrolide susceptibility over time has been noted particularly in Streptococcus pneumoniae and Staphylococcus aureus. Similarly, decreased susceptibility has been observed among Streptococcus viridans and Streptococcus agalactiae (Group B) streptococcus against other macrolides and lincosamides.

Breakpoints

Azithromycin susceptibility breakpoints for typical bacterial pathogens, as published by EUCAST are:

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Table: Antibacterial spectrum of Azithromycin

* Methycillin-resistant staphylococci have a very high prevalence of acquired resistance to macrolides and have been placed here because they are rarely susceptible to azithromycin.

Absorption

Bioavailability after oral administration is approximately 37%. Peak plasma concentrations are attained 2 to 3 hours after taking the medicinal product.

Distribution

Orally administered azithromycin is widely distributed throughout the body. In pharmacokinetic studies it has been demonstrated that the concentrations of azithromycin measured in tissues are noticeably higher (as much as 50 times) than those measured in plasma, which indicates that the agent strongly binds to tissues.

Binding to serum proteins varies according to plasma concentration and ranges from 12% at 0.5 microgram/ml up to 52% at 0.05 microgram azithromycin/ml serum. The mean volume of distribution at steady state (VVss) has been calculated to be 31.1 l/kg.

Elimination

The terminal plasma elimination half-life closely reflects the elimination half-life from tissues of 2-4 days.

Approximately 12% of an intravenously administered dose of azithromycin is excreted unchanged in urine within the following three days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Also in bile, ten metabolites were detected, which were formed through N- and O- demethylation, hydroxylation of desosamine and aglycone rings and cleavage of cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses has shown that the metabolites of azithromycin are not microbiologically active.

In animal tests, high concentrations of azithromycin have been found in phagocytes. It has also been established that during active phagocytosis higher concentrations of azithromycin are released from inactive phagocytes. In animal models this results in high concentrations of azithromycin being delivered to the site of infection.

Phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (e.g. eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) of mice, rats, and dogs given multiple doses of azithromycin. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs. The effect has been shown to be reversible after cessation of azithromycin treatment. The significance of the finding for animals and humans is unknown.

Carcinogenic potential:

Long-term studies in animals have not been performed to evaluate carcinogenic potential as the drug is indicated for short-term treatment only and there were no signs indicative of carcinogenic activity.

Mutagenic potential:

There was no evidence of a potential for genetic and chromosome mutations in in-vivo and in-vitro test models.

Reproductive toxicity:

In animal studies for embryotoxic effects of the substance, no teratogenic effect was observed in mice and rats. In rats, azithromycin doses of 100 and 200 mg/kg bodyweight/day led to mild retardation of foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardation following treatment with 50 mg/kg/day azithromycin and above was observed.

Tablet core

Calcium hydrogen phosphate

croscarmellose sodium

Maize starch

Povidone K-90

Sodium Lauryl Sulfate

Magnesium Stearate

Colloidal anhydrous silica ,

Coating

Opadry I YS-IR -7003

Not applicable.

Store below 30 °C.

Do not refrigerate.

Store in the original pack to protect from light and moisture.

AZIMAC 250 mg: Opaque PVC-PVDC film / Aluminium foil blister pack of 6 tablets.

AZIMAC 500 mg: Opaque PVC-PVDC film / Aluminium foil blister pack of 3 tablets.

Not applicable.